ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7174C>T (p.Arg2392Trp) (rs149827260)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166522 SCV000217322 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000168469 SCV000219169 uncertain significance Ataxia-telangiectasia syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 2392 of the ATM protein (p.Arg2392Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs149827260, ExAC 0.1%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 186868). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000590313 SCV000292480 uncertain significance not provided 2019-01-08 criteria provided, single submitter clinical testing This variant is denoted ATM c.7174C>T at the cDNA level, p.Arg2392Trp (R2392W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant was reported in a multiethnic exome array study; however, no statistically significant association with breast cancer was identified after correcting for multiple comparisons (Haiman 2013). ATM Arg2392Trp was observed at an allele frequency of 0.07% (17/24032) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located in the FAT domain (Stracker 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Arg2392Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000166522 SCV000682393 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000855629 SCV000694346 uncertain significance not specified 2019-08-27 criteria provided, single submitter clinical testing Variant summary: ATM c.7174C>T (p.Arg2392Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251310 control chromosomes, predominantly at a frequency of 0.00068 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than the estimated maximum for pathogenic variants in ATM causing Breast Cancer (0.00068 vs 0.001), allowing no conclusion about variant significance. c.7174C>T has been reported in the literature in individuals affected with Breast Cancer (Haiman_2013, Young_2015). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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